Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801.

Neuregulin-1 (NRG1) is a well-recognized risk gene for schizophrenia and is often implicated in the neurodevelopmental hypothesis of this illness. Alternative splicing and proteolytic processing of the NRG1 gene produce more than 30 structural variants; however, the neuropathological roles of individual variants remain to be characterized. On the basis of the neurodevelopmental hypothesis of schizophrenia, we administered eNRG1 (0.1~1.0 µg/g), a core epidermal growth factor-like (EGF) domain common for all splicing NRG1 variants, to neonatal mice and compared their behavioral performance with mice challenged with a full mature form of type 1 NRG1 variant. During the neonatal stage, recombinant eNRG1 protein administrated from the periphery passed the blood-brain barrier and activated its receptor (ErbB4) in the brain. In adults, the mice receiving the highest dose exhibited lower locomotor activity and deficits in prepulse inhibition and tonedependent fear learning, although the hearing reduction of the eNRG1-treated mice may explain these behavioral deficits. Neonatal eNRG1 treatment also significantly potentiated MK-801-driven locomotor activity in an eNRG1 dose-dependent manner. In parallel eNRG1 treatment enhanced MK-801-driven c-Fos induction and decreased immunoreactivity for NMDA receptor subunits in adult brain. In contrast, mice that had been treated with the same molar dose of a full mature form of type 1 NRG1 as neonates did not exhibit hypersensitivity to MK-801. However, both animal models exhibited similar hypersensitivity to methamphetamine. Collectively, our findings suggest that aberrant peripheral NRG1 signals during neurodevelopment alter later behavioral traits and auditory functions in the NRG1 subtype-dependent manner.

ErbB inhibitors ameliorate behavioral impairments of an animal model for schizophrenia: implication of their dopamine-modulatory actions.

Ligands for ErbB receptors, including epidermal growth factor (EGF) and neuregulin-1, have a neurotrophic activity on midbrain dopaminergic neurons and are implicated in the pathophysiology of schizophrenia. Although ErbB kinase inhibitors ameliorate behavioral deficits of the schizophrenia model that was established by hippocampal lesioning of rat pups, the antipsychotic action of ErbB kinase inhibitors and its general applicability to other models are not fully characterized. Using a different animal model, here, we examined whether and how ErbB kinase inhibitors ameliorate the behavioral endophenotypes relevant to schizophrenia. The animal model for schizophrenia was prepared by exposing neonatal rats to the cytokine EGF. Intraventricular infusion of the ErbB1 inhibitors ZD1839 and PD153035 in these animals ameliorated the deficits in startle response and prepulse inhibition in a dose-dependent manner. The deficits of latent inhibition of fear learning were also alleviated by ZD1839 with its limited effects on body weight gain or locomotor activity. ZD1839 infusion also decreased the busting activity of nigral dopamine (DA) neurons and reduced pallidal DA metabolism, a result that mimics the anti-dopaminergic profile of risperidone and haloperidol in this brain region. ErbB inhibitors appear to have anti-dopaminergic actions to alleviate some of the behavioral deficits common to animal models for schizophrenia.

DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia.

We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD.

Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia.

Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures or other phenotypic features of neurons and glial cells. Collectively, our findings provide novel insights into neurotrophic contribution of NRG1 to dopaminergic maldevelopment and schizophrenia pathogenesis.

Measurement and comparison of serum neuregulin 1 immunoreactivity in control subjects and patients with schizophrenia: an influence of its genetic polymorphism.

Neuregulin-1 (NRG1) gene is implicated in the etiology or neuropathology of schizophrenia, although its biological contribution to this illness is not fully understood. We have established an enzyme-linked immunosorbent assay (ELISA), which recognizes the NRG1beta1 immunoglobulin-like (Ig) domain, and measured soluble Ig-NRG1 immunoreactivity in the sera of chronic schizophrenia patients (n = 40) and healthy volunteers (n = 59). ELISA detected remarkably high concentrations of Ig-NRG1 immunoreactivity in human serum (mean 5.97 +/- 0.40 ng/mL, ~213 +/- 14 pM). Gender and diagnosis exhibited significant effects on serum Ig-NRG1 immunoreactivity. Mean Ig-NRG1 immunoreactivity in the schizophrenia group was 63.2% of that measured in the control group. Ig-NRG1 immunoreactivity in women was 147.1% of that seen in men. We also attempted to correlate six SNPs of NRG1 genome with serum Ig-NRG1 immunoreactivity. Analysis of covariance with compensation for gender identified a significant interaction between diagnosis and SNP8NRG243177 allele. The T allele of this SNP significantly contributed to the disease-associated decrease in Ig-NRG1 immunoreactivity. Although we hypothesized a chronic influence of antipsychotic medications, there was no significant effect of chronic haloperidol treatment on serum Ig-NRG1 immunoreactivity in monkeys. These findings suggest that serum NRG1 levels are decreased in patients with chronic schizophrenia and influenced by their SNP8NRG243177 alleles.

In situ hybridization reveals developmental regulation of ErbB1-4 mRNA expression in mouse midbrain: implication of ErbB receptors for dopaminergic neurons.

Although epidermal growth factor (EGF) and neuregulin-1 are neurotrophic factors for mesencephalic dopaminergic neurons and implicated in schizophrenia, the cellular localization and developmental regulation of their receptors (ErbB1-4) remain to be characterized. Here we investigated the distributions of mRNA for ErbB1-4 in the midbrain of the developing mouse with in situ hybridization and immunohistochemistry. The expression of ErbB1 and ErbB2 mRNAs was relatively high at the perinatal stage and frequently colocalized with mRNA for S100beta and Olig2, markers for immature astrocytes or oligodendrocyte precursors. Modest signal for ErbB1 mRNA was also detected in a subset of dopaminergic neurons. ErbB3 mRNA was detectable at postnatal day 10, peaked at postnatal day 18, and colocalized with 2',3'-cyclic nucleotide 3'-phosphodiesterase, a marker for oligodendrocytes. In contrast, ErbB4 mRNA was exclusively localized in neurons throughout development. Almost all of ErbB4 mRNA-expressing cells (94%-96%) were positive for tyrosine hydroxylase in the substantia nigra pars compacta but 66%-78% in the ventral tegmental area and substantia nigra pars lateralis. Conversely, 92%-99% of tyrosine hydroxylase-positive cells expressed ErbB4 mRNA. The robust and restricted expression of ErbB4 mRNA in the midbrain dopaminergic neurons suggests that ErbB4 ligands, neuregulin-1 and other EGF-related molecules, contribute to development or maintenance of this neuronal population.

Epidermal growth factor administered in the periphery influences excitatory synaptic inputs onto midbrain dopaminergic neurons in postnatal mice.

Epidermal growth factor (EGF) has a neurotrophic activity on developing midbrain dopaminergic neurons. We investigated developmental effects of peripheral EGF administration on dopaminergic neurons in midbrain slice preparations containing ventral tegmental area (VTA). Subcutaneous EGF administration to mouse neonates triggered phosphorylation of EGF receptors (ErbB1 and ErbB2) in the midbrain region, suggesting its penetration through the blood-brain barrier. We repeated EGF administration in postnatal mice and examined synaptic transmission in the VTA with electrophysiological recordings. Subchronic EGF treatment increased the amplitude of field excitatory postsynaptic potentials evoked by stimulation of the anterior VTA. To analyze the EGF effect at a single cell level, dopaminergic neurons were identified by their characteristic hyperpolarizing activated currents in whole cell recording. In these dopaminergic neurons, EGF effects the amplitude of spontaneous miniature excitatory postsynaptic currents (mEPSCs) without affecting their frequency. In agreement, EGF also enhanced the AMPA/NMDA ratio of evoked EPSCs in the dopaminergic neurons. In contrast, EGF effects on mEPSCs of neighboring neurons not exhibiting hyperpolarizing activated currents were modest or insignificant. Thus, these results suggest that circulating EGF substantially influences the physiological properties of developing midbrain dopaminergic neurons in perinatal and postnatal mice.

The anthraquinone derivative Emodin ameliorates neurobehavioral deficits of a rodent model for schizophrenia.

Abnormality in cytokine signaling is implicated in the neuropathology of schizophrenia. Previously, we established an animal model for schizophrenia by administering epidermal growth factor (EGF) to neonatal rats. Here we investigated effects of the anthraquinone derivatives emodin (3-methyl-1,6,8-trihydroxyanthraquinone) and sennoside (bis-[D: -glucopyranosyl-oxy]-tetrahydro-4,4'-dihydroxy-dioxo[bianthracene]-2,2'-dicarboxylic acid) on behaviors of this model and EGF signaling. Subchronic oral administration of emodin (50 mg/kg) suppressed acoustic startle responses and abolished prepulse inhibition (PPI) deficits in this rodent model. ANCOVA revealed that emodin had distinct effects on PPI and startle responses. In contrast, sennoside (50 mg/kg) had no effects. Emodin attenuated weight gain initially during treatment but had no apparent effect on weight gain and locomotor activity thereafter. Application of emodin to neocortical cultures attenuated the phosphorylation of ErbB1 and ErbB2. We conclude that emodin can both attenuate EGF receptor signaling and ameliorate behavioral deficits. Therefore, emodin might be a novel class of a pro-drug for anti-psychotic medication.

The cellular and behavioral consequences of interleukin-1 alpha penetration through the blood-brain barrier of neonatal rats: a critical period for efficacy.

Proinflammatory cytokines circulating in the periphery of early postnatal animals exert marked influences on their subsequent cognitive and behavioral traits and are therefore implicated in developmental psychiatric diseases such as schizophrenia. Here we examined the relationship between the permeability of the blood-brain barrier to interleukin-1 alpha (IL-1 alpha) in neonatal and juvenile rats and their later behavioral performance. Following s.c. injection of IL-1 alpha into rat neonates, IL-1 alpha immunoreactivity was first detected in the choroid plexus, brain microvessels, and olfactory cortex, and later diffused to many brain regions such as neocortex and hippocampus. In agreement, IL-1 alpha administration to the periphery resulted in a marked increase in brain IL-1 alpha content of neonates. Repeatedly injecting IL-1 alpha to neonates triggered astrocyte proliferation and microglial activation, followed by behavioral abnormalities in startle response and putative prepulse inhibition at the adult stage. Analysis of covariance with a covariate of startle amplitude suggested that IL-1 alpha administration may influence prepulse inhibition. However, adult rats treated with IL-1 alpha as neonates exhibited normal learning ability as measured by contextual fear conditioning, two-way passive shock avoidance, and a radial maze task and had no apparent sign of structural abnormality in the brain. In comparison, when IL-1 alpha was administered to juveniles, the blood-brain barrier permeation was limited. The increases in brain IL-1 alpha content and immunoreactivity were less pronounced following IL-1 alpha administration and behavioral abnormalities were not manifested at the adult stage. During early development, therefore, circulating IL-1 alpha efficiently crosses the blood-brain barrier to induce inflammatory reactions in the brain and influences later behavioral traits.

Gene expression profiling of primate neocortex: molecular neuroanatomy of cortical areas.

One hundred years have passed since Brodmann's mapping of the mammalian neocortex. Solely on the basis of morphological observations, he envisaged the conservation and differentiation of cortical areal structures across various species. We now know that neurochemical, connectional and functional heterogeneity of the neocortex accompanies the morphological divergence observed in such cytoarchitectonic studies. Nevertheless, we are yet far from fully understanding the biological significance of this cortical heterogeneity. In this article, we review our past works on the gene expression profiling of the postnatal primate cortical areas, by quantitative real-time polymerase chain reaction (PCR), DNA array, differential display PCR and in situ hybridization analyses. These studies revealed both the overall homogeneity of gene expression across different cortical areas and the presence of a small number of genes that show markedly area-specific expression patterns. In situ hybridization showed that, among such genes, occ1 and retinol-binding protein (RBP) mRNAs are selectively expressed in the neuronal populations that seem to be involved in distinct neural processing such as sensory reception (for occ1) and associative function (for RBP). Such a molecular neuroanatomical approach has the promise to provide an important link between structure and function of the cerebral cortex.

ErbB1 receptor ligands attenuate the expression of synaptic scaffolding proteins, GRIP1 and SAP97, in developing neocortex.

Scaffolding proteins containing postsynaptic density-95/discs large/zone occludens-1 (PDZ) domains interact with synaptic receptors and cytoskeletal components and are therefore implicated in synaptic development and plasticity. Little is known, however, about what regulates the expression of PDZ proteins and how the levels of these proteins influence synaptic development. Here, we show that ligands for epidermal growth factor receptors (ErbB1) decrease a particular set of PDZ proteins and negatively influence synaptic formation or maturation. In short-term neocortical cultures, concentrations of epidermal growth factor and amphiregulin (2-9 pM) decreased the expression of glutamate receptor interacting protein 1 (GRIP1) and synapse-associated protein 97 kDa (SAP97) without affecting postsynaptic density-95 (PSD-95) levels and glial proliferation. In long-term cultures, epidermal growth factor treatment resulted in a decrease in the frequency of pan-PDZ-immunoreactive aggregates on dendritic processes. A similar activity on the same PDZ proteins was observed in the developing neocortex following epidermal growth factor administration to rat neonates. Immunoblotting revealed that administered epidermal growth factor from the periphery activated brain ErbB1 receptors and decreased GRIP1 and SAP97 protein levels in the neocortex. Laser-confocal imaging indicated that epidermal growth factor administration suppressed the formation of pan-PDZ-immunoreactive puncta and dispersed those structures in vivo as well. These findings revealed a novel negative activity of ErbB1 receptor ligands that attenuates the expression of the PDZ proteins and inhibits postsynaptic maturation in developing neocortex.

Transforming growth factor-alpha changes firing properties of developing neocortical GABAergic neurons by down-regulation of voltage-gated potassium currents.

Transforming growth factor-alpha (TGFalpha), a member of the epidermal growth factor family, has neurotrophic actions on postmitotic neurons. We examined the chronic effects of TGFalpha on the electrophysiological properties of one type of GABAergic neuron, identified by its bipolar morphology, in neocortical primary culture. Approximately 85% of the bipolar neurons were GABA-immunoreactive. In response to depolarizing current injection, the bipolar neurons usually showed tonic firing of action potential under control conditions. After treatment with TGFalpha (20 ng/ml) for 2 days, these neurons failed to generate trains of action potentials. Furthermore, the treatment altered the action potential waveforms of the bipolar neurons, including the duration and amplitude of the fast after-hyperpolarization, which implies a reduction in voltage-gated potassium currents. In contrast, TGFalpha did not affect the firing properties of pyramidal-shaped non-GABAergic neurons. Voltage-clamp recordings from the bipolar neurons indicated that chronic treatment with TGFalpha markedly decreased the current densities of slow delayed rectifier (IK) and transient voltage-gated potassium currents, whereas the treatment had no effect on voltage-gated sodium current and fast delayed rectifier potassium current densities. Reverse transcription-polymerase chain reaction analysis of potassium channel mRNA in the bipolar neurons revealed that the reduction in the IK current density was caused by Kv2.2 mRNA down-regulation. Thus, chronic treatment with TGFalpha down-regulated slow delayed rectifier and transient voltage-gated potassium currents, and in parallel, suppressed repetitive generation of action potentials in the cortical GABAergic neurons.

Brain-derived neurotrophic factor upregulates and maintains AMPA receptor currents in neocortical GABAergic neurons.

The regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors is implicated in synaptic plasticity. Although we have found that brain-derived neurotrophic factor (BDNF) triggers surface translocation of AMPA receptor proteins, the physiological significance of the BDNF effect remained to be determined. The present immunohistochemical studies revealed that cortical GABAergic neurons exhibited the most striking response to BDNF. Accordingly, we monitored AMPA-triggered currents through GABAergic neurons: Chronic BDNF treatment increased the AMPA-triggered currents but not NMDA-triggered currents in culture. In parallel, the amplitude, but not frequency, of spontaneous miniature excitatory postsynaptic currents (mEPSCs) was elevated in GABAergic neurons. In agreement, BDNF enhanced GABA release triggered by AMPA compared to the amount triggered by high potassium. Conversely, there was a significant decrease in the mEPSC amplitude of GABAergic neurons in heterozygous BDNF-knockout mice. These findings indicate that the neurotrophin enhances the input sensitivity of GABAergic neurons to facilitate their inhibitory function in the neocortex.

Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation.

Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity such as long-term potentiation (LTP), a form of synaptic correlate of learning and memory. BDNF is also implicated in learning and memory. We have demonstrated that radial arm maze training in rats for spatial learning and memory results in a significant increase in the BDNF mRNA expression in the hippocampus. Moreover, antisense BDNF oligonucleotide treatment impaired not only acquisition, but also maintenance and/or recall of spatial memory in the maze. Although these results suggest a role of BDNF for spatial memory processes, the signal transduction mechanisms that mediate the actions of BDNF remain unknown. Here we show that phosphorylation of BDNF receptor tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (PI3-K) and Akt, a target of PI3-K, in the hippocampus increased in parallel with spatial memory formation. Moreover, an activation of translational processes was suggested in the hippocampus after the maze training. When spatial learning was inhibited by antisense BDNF oligodeoxynucleotide, the activation was diminished. Chronic treatment with PI3-K inhibitor wortmannin impaired spatial learning. Our findings suggested that activation of TrkB/PI3-K and protein synthesis signaling pathway by BDNF in the hippocampus is important for spatial memory.

Neonatal perturbation of neurotrophic signaling results in abnormal sensorimotor gating and social interaction in adults: implication for epidermal growth factor in cognitive development.

Epidermal growth factor (EGF) and its structurally related proteins are implicated in the developmental regulation of various brain neurons, including midbrain dopaminergic neurons. There are EGF and EGF receptor abnormalities in both brain tissues and blood from schizophrenic patients. We administered EGF to neonatal rats to transiently perturb endogenous EGF receptor signaling and evaluated the neurobehavioral consequences. EGF-treatment-induced transient impairment in tyrosine hydroxylase expression. The animals grew normally, exhibited normal weight increase, glial growth, and gross brain structures, and later lost the tyrosine hydroxylase abnormality. During and after development, however, the rats began to display various behavioral abnormalities. Abnormal sensorimotor gating was apparent, as measured by deficits in prepulse inhibition of acoustic startle. Motor activity and social interaction scores of the EGF-treated animals were also impaired in adult rats, though not in earlier developmental stages. In parallel, there was a significant abnormality in dopamine metabolism in the brain stem of the adult animals. Gross learning ability appeared to be normal as measured by active avoidance. These behavioral alterations, which are often present in schizophrenic models, were ameliorated by subchronic treatment with clozapine. Although the molecular and/or physiologic background(s) of these behavioral abnormalities await further investigation, the results of the present experiment indicate that abnormal EGF receptor stimulation given during limited neonatal stages can result in severe and persistent cognitive/behavioral dysfunctions, which appear only in adulthood.

Brain-derived neurotrophic factor modulates glucagon secretion from pancreatic alpha cells: its contribution to glucose metabolism.

AIM: Brain-derived neurotrophic factor (BDNF) reduces plasma glucose levels in obese db/db diabetic mice and is speculated to produce its effects via the hypothalamus, the regulatory centre of satiety and the autonomic nervous system. The potential effect of BDNF directly on peripheral endocrine organs, however, remains to be clarified. Here we report the effects of BDNF on hormonal secretion from pancreatic islets of Langerhans using their isolated culture. METHODS AND RESULTS: In an immunohistochemical study, mouse pancreatic alpha cells were stained specifically with the anti-TrkB (a specific receptor for BDNF) antibody. After 7 days culture of isolated islets of the normal mouse pancreas, 10 ng/ml BDNF decreased the secretion of glucagon per 6 h significantly less than that of the control (p = 0.016). In contrast, there were no significant changes in insulin secretion or glucagon and insulin contents in the islets cultured under the same conditions. In vivo administration of BDNF (10 mg/kg/day) to normal mice for 7 days significantly decreased their food consumption (p < 0.05). The fasting plasma glucose levels were decreased on day 7 compared with day 1 more significantly in BDNF-treated mice (p = 0.043) than in pair-fed control mice (p = 0.14). In newborn BDNF-knockout mice, fasting plasma glucose levels increased in the order of homozygote, heterozygote and wild type (p = 0.033). No apparent immunohistochemical abnormality was observed for pancreatic glucagon in the BDNF-knockout mice. CONCLUSION: These data suggest that BDNF affects glucose metabolism not only with its anorectic effect but also with modulated glucagon secretion from pancreatic alpha cells.

Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients.

Epidermal growth factor (EGF) comprises a structurally related family of proteins containing heparin-binding EGF-like growth factor (HB-EGF) and transforming growth factor alpha (TGFalpha) that regulates the development of dopaminergic neurons as well as monoamine metabolism. We assessed the contribution of EGF to schizophrenia by measuring EGF family protein levels in postmortem brains and in fresh serum of schizophrenic patients and control subjects. EGF protein levels were decreased in the prefrontal cortex and striatum of schizophrenic patients, whereas the levels of HB-EGF and TGFalpha were not significantly different in any of the regions examined. Conversely, EGF receptor expression was elevated in the prefrontal cortex. Serum EGF levels were markedly reduced in schizophrenic patients, even in young, drug-free patients. Chronic treatment of animals with the antipsychotic drug haloperidol had no influence on EGF levels in the brain or serum. These findings suggest that there is abnormal EGF production in various central and peripheral tissues of patients with both acute and chronic schizophrenia. EGF might thus provide a molecular substrate for the pathologic manifestation of the illness, although additional studies are required to determine a potential link between impaired EGF signaling and the pathology/etiology of schizophrenia.

Neurotrophins induce BDNF expression through the glutamate receptor pathway in neocortical neurons.

Neurotrophins jointly exert various functions in the nervous system, including neuronal differentiation, survival, and regulation of synaptic plasticity. However, the functional interactions of neurotrophins or mechanisms through which neurotrophins regulate each other are still not clear. In the present study, brain-derived neurotrophic factor (BDNF) mRNA expression is induced by neurotrophin-4/5 (NT-4/5) and by BDNF itself in neocortical neurons. K252a, a specific tyrosine kinase (Trk) inhibitor, completely suppresses BDNF- and NT-4/5-enhanced BDNF mRNA expression. NT-4/5 significantly augments BDNF protein production, which is also reversed by K252a. When neurons are incubated with neurotrophin-3 (NT-3) or nerve growth factor (NGF), there are no significant changes in BDNF mRNA or protein expression. Interestingly, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or the N-methyl-D-aspartate (NMDA) receptor blocker AP-5 completely suppresses NT-4/5-enhanced BDNF protein production, while tetrodotoxin (TTX) only suppresses NT-4/5-enhanced BDNF production by 50%. Additionally, the mitogen activated protein (MAP) kinase inhibitor PD98059 enhances BDNF-induced glutamate receptor-1 (GluR1) protein expression, but a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 strongly reduces BDNF-induced GluR1 protein expression. Taken together, glutamate receptors are important for the regulation of BDNF expression by neurotrophins, and MAP and PI3K kinases differentially modulate AMPA receptor expression in the cortical neurons.

BDNF as an anterophin; a novel neurotrophic relationship between brain neurons.

Studies of the peripheral nervous system have led to the concept of target-derived neurotrophic support. Neurotrophic factors such as nerve growth factor are now known to act as retrograde trophic factors--retrophins--that are produced in the target cells and released to presynaptic neurons. However, using brain-derived neurotrophic factor (BDNF) tagged with green-fluorescent protein to monitor the subcellular dynamics of BDNF in neurites, Tsumoto and colleagues have provided persuasive visual evidence that BDNF can be released at the synapses of brain neurons in an activity-dependent manner to act on postsynaptic neurons. Accordingly, BDNF serves as an anterophin to regulate postsynaptic development and plasticity in the central nervous system.

The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain.

Memantine is a medium-affinity uncompetitive N-methyl-d-aspartate receptor antagonist and has been clinically used as a neuroprotective agent to treat Alzheimer's and Parkinson's diseases. We have examined the effect of memantine (ip 5-50 mg/kg; 4 h) on the expression of brain-derived neurotrophic factor (BDNF) and trkB receptor mRNAs in rat brain by in situ hybridization. Memantine at a clinically relevant dose markedly increased BDNF mRNA levels in the limbic cortex, and this effect was more widespread and pronounced at higher doses. Effects of memantine on BDNF mRNA were also reflected in changes in BDNF protein levels. Moreover, memantine induced isoforms of the BDNF receptor trkB. Taken together, these data suggest that the neuroprotective properties of memantine could be mediated by the increased endogenous production of BDNF in the brain. These findings may open up new possibilities of pharmacologically regulating the expression of neurotrophic factors in the brain.